Abstract Retinoblastoma (RB) is a rare (micro-orphan disease) intraocular cancer in infants and children (typically diagnosed between birth and 5 years of age). See FDA OOPD orphan drug letter designation for RB in Appendix documents. Approximately, 250 new cases are diagnosed annually in the United States. Current standard treatment of affected children consists of either removing the one affected eye (in the case of unilateral disease), or by giving systemic chemotherapy for a period of 6-9 months, or by giving multiple regional (intra-arterial) chemotherapy (IAC) infusions. Systemic chemotherapy is associated with bone-marrow toxicity and relatively high costs. External beam radiotherapy is no longer standard primary therapy. There has never been an FDA approved intervention for Rb. Episcleral Topotecan (IND #112785) is a novel system for making possible the sustained local delivery of Topotecan directly to the interior of the eye without breaching the eye wall (by injection or incision) while sequestering Topotecan from washout to peripheral circulation. Local Episcleral Topotecan may reduce or eliminate the need for systemic chemotherapy. Inside the impermeable silicone episcleral device, the contents of the drug reservoir are maintained in direct contact with a broad expanse of the outer surface of the eye wall (the episclera), greatly facilitating the net passive unidirectional transscleral diffusion of the drug to the intraocular tumor inside the eye. Episcleral Topotecan enables sustained- release delivery of Topotecan with continuous-high-dose Topotecan retinal delivery while eliminating detectable system exposure and systemic toxicity. This FDA Orphan Drug Grant application requests funding to support Phase I clinical trials in patients with advanced unilateral group D retinoblastoma at presentation. In developing countries as many as half of all children diagnosed with retinoblastoma care are abandoned by the family for cultural or social reasons (Kumar, A., et al. (2013). Causes, outcome and prevention of abandonment in retinoblastoma in India?Pediatr Blood Cancer 60(5): 771-775). Current options for the primary treatment of RB children include, enucleation, systemic chemotherapy, and IAC. These therapeutic options are invasive, costly and associated with significant side effects. Episcleral Topotecan offers a potential therapeutic avenue that is less invasive and less costly with far fewer side effects. It also could be the first FDA-approved therapy for this micro-orphan childhood disease. Under Emergency Use protocol, we've treated our first RB patient. This child had failed multiple cycles of systemic chemo and IAC. The child had >10 refractory tumors and vitreous seeds in his remaining eye. Post Episcleral Topotecan placement, all tumors and vitreous seeds were resolved by day 28 and all but two tumors were resolved by day 12. As of day 98 EUA, there was no recurrence. There was no systemic toxicity and there was no ocular toxicity other than grade 1 vitreous hemorrhage (consider normal response to tumor response/regression). See letter and retcam images from Brenda Gallie, MD in Appendix Documents.